Lack of age-related clinical progression in PGC-1α-deficient mice – implications for mitochondrial encephalopathies

Abstract

Impaired peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) function has been demonstrated in several neurodegenerative diseases, and murine whole-body knockouts of PGC-1α have been considered as models for Huntington's disease. Recent neuropathological studies, however, rather propose these animals to be morphological models of mitochondrial encephalopathies, with special reminiscence of Kearns-Sayre syndrome. PGC-1α-deficient animals have already been subjected to behavioral assessments; however, the contradictory findings and the paucity of data assessing long-term progression necessitated further examinations. This study provides a comprehensive neurological phenotypic profiling of full-length-(FL-)PGC-1α-deficient mice in a broad age spectrum, with special focus on previously controversial findings, the issue of long-term phenotypic progression, the histopathological assessment of previously non-characterized tissues of potential clinicopathological relevance, and the gene expression profile of novel brain-specific isoforms of PGC-1α. Our findings demonstrate moderate hypomotility with signs of gait and trunk ataxia in addition to severe impairments in coordination and muscle strength in FL-PGC-1α-deficient mice, phenotypic features consistent of a mitochondrial disease. Intriguingly, however, these early alterations did not progress with age, the understanding of which may unveil mechanisms of potential therapeutic relevance, as discussed. The observed phenotype did not associate with retinal or spinal cord alterations, and was accompanied by mild myopathic changes. Based on these, FL-PGC-1α-deficient mice can be regarded not only as morphological but behavioral models of mitochondrial encephalopathies, with an important temporal limitation that has now been clarified. The mechanisms capable of halting a potentially lethal phenotype are to be unveiled, as they may hold therapeutic value for mitochondrial diseases.

Non-motor Behavioral Alterations of PGC-1α-Deficient Mice – A Peculiar Phenotype With Slight Male Preponderance and No Apparent Progression

“…These knockout mice (Leone et al, 2005) lack the expression of the FL-PGC-1α protein but express an N-terminal fragment of 254 amino acids (Chang et al, 2012), and have recently been comprehensively characterized in terms of neuropathological alterations and motor phenotype (Szalardy et al, 2013, 2016a,b). Similarly to that reported before (Szalardy et al, 2016a), the experimental animals of each study cohort were randomized from a population ranging through a wide spectrum of age (12–91 w, overall medians: 48.6 w FL-PGC-1α -/- vs. 47.9 w wild-type) to create age- and sex-matched wide-age-range cohorts.…”

“…These knockout mice (Leone et al, 2005) lack the expression of the FL-PGC-1α protein but express an N-terminal fragment of 254 amino acids (Chang et al, 2012), and have recently been comprehensively characterized in terms of neuropathological alterations and motor phenotype (Szalardy et al, 2013, 2016a,b). Similarly to that reported before (Szalardy et al, 2016a), the experimental animals of each study cohort were randomized from a population ranging through a wide spectrum of age (12–91 w, overall medians: 48.6 w FL-PGC-1α -/- vs. 47.9 w wild-type) to create age- and sex-matched wide-age-range cohorts. The FL-PGC-1α -/- mice strain developed on C57Bl/6J background were originally generated in the Kelly Lab (Sanford-Burnham Institute for Medical Research at Lake Nona, Orlando, FL, United States) and the founders of the FL-PGC-1α -/- and +/+ populations bred in our institute were a kind gift from Albert C. Ludolph and Patrick Weydt from the Department of Neurology, University of Ulm, Ulm, Germany, as littermates born from +/- breeding pairs.…”

“…Total time spent in immobility (s) was measured by the experimenter using a stopwatch, and was used for statistical analysis. The animals in this cohort were phenotyped for grip strength 3 months prior to the TST with a method previously described (Szalardy et al, 2016a), and based on the non-progressive feature of weakness in these mice, its measure was used to control for the potential confounding effect of muscle weakness in the observed immobility.…”

“…Several studies with a number of different molecular genetic approaches have been published phenotyping different PGC-1α-deficient murine strains in the past decade (i.e., complete/incomplete whole-body, organ- or cell type-specific, and conditional/germline knockout strains). These together delineated a phenotype rather reminiscent of a mitochondrial disease, with prominent spongiform intramyelin brain vacuolation, brainstem and cerebellar gliosis, and Purkinje cell loss in the CNS, accompanied by mild myopathic changes in the skeletal muscle (Lucas et al, 2012, 2014b; Szalardy et al, 2013, 2016a,b). These neuropathological hallmarks are accompanied by reduced locomotion, muscle weakness, and ataxia (Lucas et al, 2012, 2014b; Szalardy et al, 2016a), a motor phenotype intriguingly not found to progress with age (Lucas et al, 2012; Szalardy et al, 2016a).…”

“…These together delineated a phenotype rather reminiscent of a mitochondrial disease, with prominent spongiform intramyelin brain vacuolation, brainstem and cerebellar gliosis, and Purkinje cell loss in the CNS, accompanied by mild myopathic changes in the skeletal muscle (Lucas et al, 2012, 2014b; Szalardy et al, 2013, 2016a,b). These neuropathological hallmarks are accompanied by reduced locomotion, muscle weakness, and ataxia (Lucas et al, 2012, 2014b; Szalardy et al, 2016a), a motor phenotype intriguingly not found to progress with age (Lucas et al, 2012; Szalardy et al, 2016a). Despite the fact that most of the above listed human CNS disorders associate with non-motor features, only few studies have so far addressed non-motor phenotypic alterations in PGC-1α-deficient animals, providing in part contradictory results from different knockout strains, with each focusing on particular aspects (Leone et al, 2005; Agudelo et al, 2014; Lucas et al, 2014a; Bartley et al, 2015).…”